The long-term goal of the proposed research is to understand the molecular basis for innate immune resistance in the snail, Biomphalaria glabrata, to infection by larvae of the blood fluke, Schistosoma mansoni, causative agent of human hepatosplenic schistosomiasis. These snails serve as essential intermediate hosts in parasite transmission to the human host. However, in inbred strains of B. glabrata expressing the resistant (R) phenotype, early-developing schistosome larvae (primary sporocysts) are destroyed by a rapid cellular response involving the accumulation and adherence of circulating phagocytic cells (hemocytes) around sporocysts forming multilayered capsules. By contrast, hemocytes from susceptible (S) B. glabrata do not encapsulate sporocysts in vivo, and, although capable of in vitro larval adherence, fail to mount effective parasite killing responses under in vitro conditions. Based on these distinctive cellular behaviors, it is hypothesized that hemocytes from S and R strain snails possess a subset of unique (i.e., strain-specific) surface membrane receptors that are responsible for initial binding (pattern recognition) to the larval surface tegument or its secreted products (ESP), thereby providing the initiating signal for either hemocyte immune activation or inhibition of immune responsiveness. Results of research performed during the last grant period strongly implicate carbohydrate (CHO)-binding hemocyte lectin-like receptors (LRs) as primarily responsible for mediating initial binding interactions with the sporocyst tegument and secreted ESP. Therefore, the current project will focus on the isolation and molecular characterization of parasite-reactive LRs expressed on S and R strain hemocytes, determining the molecular diversity of LRs within and between S and R cells, characterizing signal transduction pathways triggered as a result of CHO-LR binding interactions, and exploring the role of naturally-occurring larval CHO, especially fucosylated oligosaccharides, as targets of host cell recognition or in modulating hemocyte function. Because of shared CHO-binding characteristics, the B. glabrata embryonic (Bge) cell line will be employed as a valuable comparative model for hemocyte LR structure and function. It is anticipated that information generated in this project will provide important insights into the mechanisms of pathogen immune recognition, which may eventually lead to more effective and novel methods for controling invertebrate vectors of human disease.